P90RSK inhibition ameliorates TGF-β1 signaling and pulmonary fibrosis by inhibiting Smad3 transcriptional activity

Suji Kim, Jung Hwa Han, Sujin Kim, Heejung Lee, Jae Ryong Kim, Jae Hyang Lim, Chang Hoon Woo

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background/Aims: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-β1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-β1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. Methods: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. Results: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-β1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-β1-induced smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation and nuclear translocation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. Conclusion: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.

Original languageEnglish
Pages (from-to)195-210
Number of pages16
JournalCellular Physiology and Biochemistry
Volume54
Issue number2
DOIs
StatePublished - 2020

Keywords

  • ECM
  • EMT
  • P90RSK
  • Pulmonary fibrosis
  • TGF-β1

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